Solid active compound inclusions in polymeric materials have already been known for a relatively long time and are employed in pharmaceuticals technology for pursuing various aims. One possibility of systematization of such polymer inclusions from a pharmaceutical standpoint is classification into fast-releasing drug forms and drug forms with modified or sustained release.
Polymer inclusions in fast-releasing drug forms are, as a rule, used to accelerate dissolution of the active compound in the fluids of the gastrointestinal tract. According to Noyes and Whitney, the rate of dissolution of a solid active compound is proportional to the active surface area A of the solid and the difference between the saturation concentration C.sub.s and the actual active compound concentration C according to the equation ##EQU1##
in which V is the volume of fluid and the constant k.sub.1 results from the diffusion coefficient D of the active compound in the fluid and the thickness h of the stationary diffusion layer from the formula.
One obvious pharmaceutical possibility for increasing the rate of dissolution of active compounds accordingly lies in increasing the surface area A, for example by micronization. In the case of poorly wettable active compounds, an effective increase in the surface area, according to the above equation (I), can also be achieved by addition of wetting agents, since non-wetted surfaces are not included in A.
At a very low solubility C.sub.s of the active compound, however, such measures by themselves do not always lead to the goal, since the difference (C.sub.s -C) is very small and causes only a low rate of dissolution. In many of these cases, a significant improvement can be achieved by inclusion of the active compounds in polymers as solid solutions.
For example, U.S. Pat. No. 4,151,273 indicates a route for inclusion of the sparingly soluble active compound griseofulvin in polyethylene glycol as a solid solution, with which faster dissolution of the active compound in the gastrointestinal tract and therefore better bioavailability can be achieved after peroral administration than in the case of conventional formulations. Other examples of solid solutions of active compounds are to be found in J. Pharm. Sci., 54, pages 1145-1148 (1965).
Active compound inclusions in the form of solid dispersions in hydrophilic polymers can also have a positive effect on dissolution of the active compound. For example, U.S. Pat. No. 4,933,360 describes a rapidly soluble solid dispersion of chlorthalidone in polyvinylpyrrolidone which has led to significantly improved absorption of the active compound in subjects, compared with commercially available formulations.
Conversely, a significant delay in the release or in the dissolution of the active compound can be achieved by inclusion of active compounds in less readily water-soluable polymers.
These formulations can be classified into erodable and erosion-resistant matrices. Erodable matrices are to be understood as meaning those which either dissolve slowly or undergo another type of breakdown of the mass in the course of the release. In these cases, the active compound is as a rule released chiefly at the margins of the polymer. On the other hand, erosion-resistant matrices are largely retained over the course of the release; their solubility is very low and coherence high. Active compounds are released from them by diffusion, and for this reason such formulations are also called diffusion matrices.
Various processes are known for the preparation of these formulations. Mention may be made, inter alia, of so-called coprecipitates, coevaporates, coextrudates and sprayed and fused inclusions (Sucker et al., Pharmazeutische Technologie [Pharmaceutical technology], Thieme Verlag 1991, page 250 et seq.). The expert is also familiar with further processing of such inclusions by comminution to powders, mixing with further auxiliaries and subsequent tablet-making or introduction into hard gelatin capsules, if they do not lead directly to drug forms which can be administered, as in the case of some coextrudates (see, for example, U.S. Pat. No. 4,933,360). In addition, the conventional drug forms of tablet and hard gelatin capsule have the advantage that extremely efficient manufacturing technologies are available in respect of metering accuracy, production rate and profitability.
Disadvantages of the prior art are the considerable expenditure on comminution of the polymer inclusions before further processing to the final drug form. Depending on the material, the mill used and the grinding conditions, comminution of the bulk goods leads to particles of different size and different shape. From the point of view of modern requirements of the purity of medicaments, mills are usually to be rejected because of their abrasion of material. With the expensive comminution processes, there is the risk of changing the physicochemical state, for example by stress-initiated thermodynamic stabilization of originally vitreous-amorphous inclusions by crystallization or, in the case of solid suspensions, even by substantial separation of the active compound and polymer. Such serious changes can be counteracted by the choice of grinding conditions, it being necessary to avoid high stresses on the formulation, and the degree of comminution tending to be kept low. As a result, pellet-like particles of spherical to irregular shape are obtained which, nevertheless, have the disadvantage that the ratio of their spatial extent to the surface area can considerably impair release of the active compound. It can thus be explained why the rate of release of an active compound from pellet-like particles of a polymer which effects sustained release, and in which it is included, decreases constantly, after a relatively rapid initial release of the active compound located close to the surface of the particles, as a result of the continuously increasing diffusion zones in the polymer. According to the current prior art, this effect of increasing diffusion zones can be bypassed only by extremely fine grinding of the inclusion material, which is accompanied by the disadvantages and risks mentioned.